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PubMed2005

Local peroxynitrite formation contributes to early control of Cryptosporidium parvum infection.

In intestinal inflammation, mucosal injury is often exacerbated by the reaction of NO with neutrophil-derived superoxide to form the potent oxidant peroxynitrite. Peroxynitrite also has antimicrobial properties that aid in the killing mechanism of macrophages and neutrophils. Cryptosporidium parvum parasitizes intestinal epithelium, resulting in loss of epithelial cells and mucosal inflammation. Synthesis of NO is significantly increased and arises from the induced expression of inducible nitric oxide synthase (iNOS) by the infected epithelium. Inhibition of iNOS results in intensified epithelial parasitism and oocyst excretion. We hypothesized that formation of peroxynitrite is restricted to sites of iNOS expression by the epithelium and contributes to host defense in C. parvum infection. Accordingly, the location and biological effects of peroxynitrite formation were examined in neonatal piglets infected with C. parvum. Infected piglets were treated daily with a selective iNOS inhibitor [L-N6-(1-iminoethyl)-lysine] or one of two peroxynitrite scavengers [5,10,15,20-tetrakis(N-methyl-4'-pyridyl)porphyrinato iron(III) or uric acid] or received vehicle. At peak infection, peroxynitrite formation was restricted to sites of iNOS expression by parasitized epithelium and lamina propria of the apical villi. Peroxynitrite formation was dependent on iNOS activity and was inhibited by treatment with peroxynitrite scavengers. Scavengers increased the number of intracellular parasites and the number of infected epithelial cells present per villus and significantly exacerbated oocyst excretion. Recovery from infection was not delayed by ongoing treatment with scavenger. The present results are the first to demonstrate an in vivo role for peroxynitrite formation in acute mucosal defense against a noninvasive intestinal epithelial pathogen.

Animals↗
PubMed2007

CD4(+) T lymphocytes mediate colitis in HLA-B27 transgenic rats monoassociated with nonpathogenic Bacteroides vulgatus.

BACKGROUND: HLA-B27/beta2 microglobulin transgenic (TG) rats develop spontaneous colitis when raised under specific pathogen-free (SPF) conditions or after mono-association with Bacteroides vulgatus (B. vulgatus), whereas germ-free TG rats fail to develop intestinal inflammation. SPF HLA-B27 TG rnu/rnu rats, which are congenitally athymic, remain disease free. These results indicate that commensal intestinal bacteria and T cells are both pivotal for the development of colitis in TG rats. However, it is not known if T cells are also required in the induction of colitis by a single bacterial strain. The aim of this study was therefore to investigate the role of T cells in the development of colitis in B. vulgatus-monoassociated HLA-B27 TG rats. METHODS: HLA-B27 TG rnu/rnu and rnu/+ rats were monoassociated with B. vulgatus for 8-12 weeks. CD4(+) T cells from mesenteric lymph nodes (MLNs) of B. vulgatus-monoassociated rnu/+ TG donor rats were transferred into B. vulgatus-monoassociated rnu/rnu TG recipients. RESULTS: B. vulgatus-monoassociated rnu/+ rats showed higher histologic inflammatory scores and elevated colonic interferon-gamma mRNA, cecal myeloperoxidase, and cecal IL-1beta levels compared to those in rnu/rnu TG rats that did not contain T cells. After transfer of CD4(+) cells from colitic B. vulgatus-monoassociated rnu/+ TG donor rats, B. vulgatus-monoassociated rnu/rnu TG recipients developed colitis that was accompanied by B. vulgatus-induced IFN-gamma production by MLN cells in vitro and inflammatory parameters similar to rnu/+ TG rats. CONCLUSIONS: These results implicate CD4(+) T cells in the development of colitis in HLA-B27 TG rats monoassociated with the nonpathogenic bacterial strain B. vulgatus.

Animals↗
PubMed1993

Intestinal permeability to [51Cr]EDTA in infectious diarrhea.

Orally administered [51Cr]EDTA was used to measure intestinal permeability in subjects with infectious diarrhea and in those without gastrointestinal complaints. [51Cr]EDTA was given to 87 subjects: 63 controls (32 normal controls, and 31 disease controls), and 24 patients with infectious diarrhea. Approximately 100 microCi of [51Cr]EDTA was given orally after an overnight fast. Urine was collected for the following 24 hr. Intestinal permeability to [51Cr]EDTA in both normal volunteers and in patients with a variety of diseases not associated with intestinal injury was low and results were in a relatively narrow range. Mean 24-hr urinary excretion of [51Cr]EDTA, calculated as a percent of the administered dose, in controls was 1.6% (0.2-3.5%). Patients with infectious diarrhea associated with invasive pathogens and/or intestinal inflammation had increased excretion of [51Cr]EDTA (mean 6.1%, P < 0.0001), with elevated excretions in 75%. These results demonstrate that intestinal infections must be considered as possible causes for increased intestinal permeability as assessed by the [51Cr]EDTA test.

Adult↗
PubMed2003

Prolonged interferon-gamma exposure decreases ion transport, NKCC1, and Na+-K+-ATPase expression in human intestinal xenografts in vivo.

IFN-gamma is elevated in intestinal inflammation and alters barrier and transport functions in human colonic epithelial cell lines, but its effects on normal human small intestinal epithelium in vivo are poorly defined. We investigated effects of prolonged IFN-gamma exposure on ion transport and expression of transporters by using human fetal small intestinal xenografts. Xenograft-bearing mice were injected with IFN-gamma, and 24 h later xenografts were harvested and mounted in Ussing chambers. Baseline potential difference (PD) was not affected by IFN-gamma treatment. However, conductance was enhanced and agonist-stimulated ion transport was decreased. IFN-gamma also decreased expression of the Na+-K+-2Cl- cotransporter and the alpha-subunit of Na+-K+-ATPase compared with controls, whereas levels of the calcium-activated Cl- channel and CFTR were unaltered. Thus prolonged exposure to IFN-gamma leads to decreased ion secretion due, in part, to decreased ion transporter levels. These findings demonstrate the implications of elevated IFN-gamma levels in human small intestine and validate the human intestinal xenograft as a model to study chronic effects of physiologically relevant stimuli.

Animals↗
PubMed2004

Effect of 5-lipoxygenase inhibition on events associated with inflammatory bowel disease in rats.

Leukotrienes play a part in inflammatory response. The unique role of the enzyme 5-lipoxygenase (5-LOX) in the production of leukotrienes makes it a likely therapeutic target for inflammatory conditions like asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD). The aim of the present study was to evaluate the effect of zileuton, an orally active selective 5-LOX inhibitor against the events associated with dextran sodium sulphate-induced colitis in a rat model of IBD. The animals were administered simultaneously zileuton (100mg/kg) or sulphasalazine (100mg/kg) orally for 7 days. On day eight, rats were sacrificed, and distal colon isolated to determine myeloperoxidase activity, in vivo superoxide dismutase activity, prostaglandin E2 levels and histological examination. Both zileuton and sulphasalazine significantly prevented the development of inflammatory events associated with colitis. The effect of zileuton was more pronounced towards reducing myeloperoxidase activity and increasing PGE2 levels in distal colon. The results show that chemotactic leukotrienes are responsible for inflammatory surge in damaged colon and, zileuton, significantly improved healing by inhibition of neutrophil recruitment and indirectly through increase in prostaglandins at the site of inflammation. It is suggested that inhibitors of 5-LOX enzyme may have useful therapeutic role in the treatment of chronic intestinal inflammation.

Animals↗
PubMed1992

Spondylarthropathy and gut inflammation: immunopathogenetic mechanisms.

In 62% of patients with spondylarthropathy (SpA) we found clinically unsuspected gut inflammation to feature acute or chronic enterocolitis on ileocolonoscopy. A proportion of patients of the latter group had subclinical Crohn's disease as demonstrated clinically, endoscopically, genetically, histologically and immunopathologically. There is a relation between the activity of the gut inflammation and clinical rheumatic symptoms. A pathogenetic mechanism is increased handling of luminal (bacterial or nutritional) antigen, hence inducing T-cell activation and intestinal inflammation. In ileal mucosal biopsies we showed two different cellular events: increased enterocytic expression of class II molecules in active inflammation and an increase of membranous (M) cells overlying lymphocytes in inflamed mucosa. Although the number of intraepithelial lymphocytes was not increased in inflammation, intraepithelial T lymphocytes had protruding processes in close apposition to the tips of epithelial plasma membranes. Lymphocytes crossing the basement membrane were a frequent finding. These features indicate that the intestinal immune response caused by increased antigen processing in the terminal ileum induces an inflammatory immunocascade responsible for the clinical picture of SpA.

Adolescent↗
PubMed2005

Effect of anemonin on NO, ET-1 and ICAM-1 production in rat intestinal microvascular endothelial cells.

Anemonin (the dilactone of cyclobutane-1, 2-diol-1, 2-diacrylic acid) was isolated from the root of Pulsatilla chinensis Regel. Pulsatilla chinensis Regel has been used in the treatment of enteritis in China for years. However, only little was known about the mechanism underlying its anti-inflammatory effects. We investigated the effect of anemonin on the release of nitric oxide (NO), endothelin-1 (ET-1) and soluble intercellular adhesion molecule-1 (sICAM-1) induced by lipopolysaccharide (LPS) in primary cultures of rat intestinal microvascular endothelial cells (RIMECs). RIMECs were challenged with 1 microg/ml LPS with or without the presence of various concentrations of anemonin (1, 5 and 10 microg/ml). Anemonin significantly inhibited the production of NO and ET-1 induced by LPS at a concentration of 5 microg/ml and at 10 microg/ml anemonin down-regulated LPS-induced sICAM-1 expression. Anemonin itself had no effect on either factor. These findings suggest that anemonin may exert some beneficial therapeutic action in intestinal inflammation, at least in part by inhibiting the production of NO, ET-1 and ICAM-1 in RIMECs and thus preventing intestinal microvascular dysfunction.

Animals↗
PubMed2026

Phytolacca acinosa Roxb. induces intestinal toxicity through the histamine-MLCK-tight junction axis: Integrated evidence from proteomics, metabolomics, intestinal organoids and epithelial barrier validation.

Phytolacca acinosa Roxb. (PR) is a saponin-rich medicinal plant associated with gastrointestinal toxicity, but the mechanisms underlying PR-induced intestinal barrier injury remain unclear. In this study, raw PR extract was analytically characterized by UPLC-ZenoTOF-MS/MS, confirming triterpenoid saponins as the predominant constituents. C57BL/6&#x202f;J mice were orally exposed to characterized PR extract (1.20 or 12.0&#x202f;g/kg for 5&#x202f;h), and Caco-2 cells and mouse intestinal organoids were used to assess epithelial toxicity and barrier disruption. Histopathology, ELISA, FITC-dextran permeability assays, immunofluorescence, CCK-8, LDH release, western blotting, DIA-based proteomics and untargeted metabolomics were integrated to define toxicological mechanisms. PR induced dose-dependent intestinal inflammation and barrier dysfunction, with the ileum as the most sensitive target. PR increased serum DAO and D-lactate and intestinal TNF-&#x3b1; and IL-1&#x3b2;, disrupted organoid morphology, enhanced epithelial permeability, and reduced ZO-1 expression. Proteomics revealed changes in inflammatory, lipid-metabolic, cytoskeletal and tight-junction pathways, including upregulation of MLCK3 and phospholipase-related proteins and downregulation of ZO-1 and ZO-2. Metabolomics identified histidine metabolism disturbance and histamine accumulation. Integrated multi-omics and pharmacological validation indicated that histamine activated the PLC/IP&#x2083;/Ca&#xb2;&#x207a;/CaM/MLCK cascade, promoting MLC phosphorylation, tight-junction disassembly and epithelial leakiness. MLCK inhibition partially restored ZO-1/ZO-2 expression and attenuated PR-induced epithelial injury. These findings identify the histamine-MLCK-tight junction axis as a key mechanism of PR-induced intestinal toxicity and support hazard identification of saponin-rich PR exposure.

Animals↗
PubMed1998

Effect of interleukin-1beta on the ascending and descending reflex in rat small intestine.

Acute inflammation of the intestine is associated with motility changes. We investigated the acute effect of inflammatory mediators such as interleukin-1beta, interleukin-2 and tumor necrosis factor-alpha (TNF-alpha) on electrically stimulated ascending and descending reflex responses of the rat small intestine. Exogenous application of interleukin-1beta caused a concentration-dependent inhibition of the oral contraction (0.1 ng/ml: -22.9+/-3.8%, 10 ng/ml: -57.0+/-7.4%, P < 0.05, n=10) but had no effect on anal relaxation. The interleukin-1 receptor antagonist alone had no significant effect on the reflex response, but prevented the inhibitory effect of interleukin-1beta (10 ng/ml: -3.9+/-11.4%, n=8). Interleukin-2 and TNF-alpha had no significant effect on the oral contractile and the anal inhibitory response (n.s., n=10). Using reverse transcriptase polymerase chain reaction (RT-PCR) the presence of mRNA of the interleukin-1 receptor was demonstrated in the rat small intestine. Preincubation of the preparation with indomethacin (10(-6) M), the histamine H1 receptor antagonist, pyrilamine (10(-8) M), and the histamine H3 receptor antagonist, clobenpropit (10(-8) M), decreased the oral contraction by 60.1+/-7.7%, 42.8+/-6.9% and 44.4+/-14.2% as well as the anal relaxation. These data suggest that acute administration of interleukin-1beta inhibits the ascending and descending contractile reflex pathway and this effect seems not to be mediated by prostaglandins or histamine receptors.

Animals↗
PubMed2003

CCR5 mediates specific migration of Toxoplasma gondii-primed CD8 lymphocytes to inflammatory intestinal epithelial cells.

BACKGROUND & AIMS: Toxoplasma gondii, an obligate intracellular parasite, can invade intestinal epithelial cells and elicit a robust Th1 immune response. In this model of intestinal inflammation, CD8(+) intraepithelial lymphocytes (IELs) secrete transforming growth factor (TGF)-beta, which appears necessary for the maintenance of homeostasis in the intestine. However, the mechanism responsible for the IEL migration to the inflamed intestine is still unclear. METHODS: An in vitro coculture cell system was used to quantify the IEL attraction by an infected intestinal epithelial cell line (m-IC(cl2)). We used CCR5-deficient mice to determine which chemokine receptor-chemokine interaction could be responsible for the recruitment of antigen-specific CD8(+) IELs to the small intestine for the promotion of parasite clearance and host recovery. RESULTS: We observed increased expression of several chemokine receptors (CCR1, CCR2, CCR5, CXCR3) in the infected ileum. In particular, CCR5 expression was markedly increased in antigen-primed CD8(+) IELs. Experiments using recombinant chemokines as well as blocking antibodies showed that macrophage inflammatory protein (MIP)-1alpha and MIP-1beta were critical for their homing. CD8(+) IELs isolated from CCR5-deficient mice (CCR5-/-), despite their high production of TGF-beta and overexpression of activation markers, were impaired in their ability to migrate in vitro to the m-IC(cl2) monolayer or in vivo to the inflamed intestine after adoptive transfer. CONCLUSIONS: Our data emphasize the biologic role of CCR5 as an important component in the migration of intraepithelial CD8(+) T cells and the regulation of the inflammatory response following parasite infection.

Animals↗
PubMed1996

Regulatory cytokines in inflammatory bowel disease.

Several immunological alterations have been described in inflammatory bowel disease, but their role in the pathogenesis of tissue damage of these disorders is not fully known. Activated immune cells produce proinflammatory and regulatory cytokines able to mediate immune mechanisms underlying intestinal inflammation in both ulcerative colitis and Crohn's disease. Although there is no evidence for an aberrant cytokine secretion in the intestinal mucosa of patients with inflammatory bowel disease, observations seem to indicate that locally released cytokines trigger the preferential differentiation of mucosal lymphocytes into TH1 or TH2 subsets. The unresponsiveness of intestinal mononuclear cells to the inhibiting effects of regulatory cytokines may, also, contribute to this differentiation.

Animals↗
PubMed2000

Local short-chain fatty acids supplementation without beneficial effect on inflammation in excluded rectum.

BACKGROUND: Rectal instillation of short-chain fatty acids (SCFA), important nutrients for the colorectal mucosa, has been suggested to be of therapeutic value in distal intestinal inflammation. METHODS: In this study nine patients with Hartmann-closed rectum after colectomy for acute colitis were investigated. In a double-blind crossover trial an enema containing SCFA or a placebo solution was administered twice daily for 3 weeks. Before entry into the protocol, after each treatment period, and 6 weeks after the study period the patients' symptoms were evaluated, rectal endoscopy was performed, histologic samples were scored, and microbiologic analyses were carried out. RESULTS: No significant differences in symptoms, in mucosal inflammation, in histologic scoring, or in microbiologic studies were found between SCFA and placebo periods. Unexpectedly, all but one patient entirely lacked coliform bacteria in the rectum. CONCLUSIONS: In this study SCFA enemas had no beneficial effect on inflammation in excluded rectum in patients earlier submitted to colectomy for colitis. However, a different rectal flora was detected in these patients.

Adult↗
PubMed1996

New insights on molecular pathways utilized by salmonella species in cell binding.

Salmonella infections are a principal source of gastroenteritis and enteric fever in a variety of animals, including humans. An essential step in the development of Salmonella pathogenesis is the entry of bacteria into non-phagocytic cells, including those that line the intestinal epithelium. As a consequence of specific cues from the host intestinal micro-environment, Salmonella entry into the intestinal epithelium is the product of a multistep process that culminates in host cell membrane ruffling, and subsequent bacterial uptake. The events that trigger the internalization event appear to require an array of bacterial secreted proteins, exemplified by the formation of bacterial surface appendages (invasomes) which are important for the induction of host-cell signal transduction pathways that lead to membrane ruffling. In addition, during intestinal disease states induced by Salmonella typhimurium, transepithelial migration of neutrophils rapidly follows attachment of the bacteria to the epithelial membrane. Current evidence indicates that the intestinal epithelium plays a key role in orchestrating the inflammatory response to surface attached S. typhimurium. In this review, we explore current insights on the molecular pathways utilized by Salmonella spp. in cell binding that are important not only in the processes of Salmonella internalization but also in the generation of signals which lead to active states of intestinal inflammation.

Animals↗
PubMed2005

Selective loss of NGF-sensitive neurons following experimental colitis.

Nerve growth factor (NGF) enhances neuronal survival during injury to the mature central and peripheral nervous systems, but its potential as a neuroprotective factor in the enteric nervous system (ENS) has not been examined. We used the trinitrobenzene sulfonic acid (TNBS)-induced model of colitis to examine if NGF-sensitive neurons were selectively spared from inflammation-induced cell loss. Immunocytochemistry of whole mounts of the rat colon showed that total myenteric neuronal number decreased by 32.9% +/- 1.4% by 35 days after inflammation. At this time, the proportion of neurons expressing both the p75 and trkA receptor decreased to 38.4% from a control value of 62.0%. The distribution of expression of neural phenotypes among the NGF receptor-expressing population was differentially affected by inflammation, with selective decrease among cholinergic excitatory neurons and calbindin-expressing neurons, and a trend to increase among inhibitory nitrergic neurons. This is evidence of a novel mechanism whereby intestinal inflammation can give rise to a permanent imbalance between excitatory and inhibitory neural pathways, thus tending to compromise intestinal function.

Animals↗
PubMed2005

Impact of COX-2 inhibitors in common clinical practice a gastroenterologist's perspective.

Non-selective NSAIDs enhance the risk of serious ulcer complications (bleeding, perforation, obstruction), hospitalization and death about 3-10-fold. The gastrointestinal side effects of NSAIDs have a considerable economical burden, since they are responsible for 5-10 billion dollars in hospitalization charges and lost work time. NSAIDs cause gastrointestinal damage by both topical and systemic effects. COX-1-mediated inhibition of prostaglandin synthesis is probably the most relevant mechanism, but NSAIDs can cause gastrointestinal injury also by COX-independent pathways. COX-2-selective inhibitors (Coxibs) such as celecoxib, rofecoxib or valdecoxib have been developed to achieve an equal relief of pain and inflammation as classical NSAIDs but without their risk of gastrointestinal side effects. Within the first three months, celecoxib became the fastest selling drug in history. The gastrointestinal safety of classical NSAIDs and Coxibs has been compared in a variety of endoscopic investigations, meta-analyses and outcome studies. In conclusion, these studies have clearly shown, that Coxibs are associated with significantly less dyspeptic symptoms, erosions, ulcers and ulcer complications. In contrast, Coxibs seem to delay gastric ulcer healing to the same extent as traditional NSAIDs. Besides their effects on the upper gastrointestinal tract, NSAIDs can cause small intestinal inflammation, ulcers of the small and large intestine, ileal dysfunction, intestinal strictures, colitis and NSAID enteropathy. In addition, NSAIDs increase the risk of lower gastrointestinal complications including bleeding, perforation and obstruction. Current data suggest, that Coxibs are associated with a significantly lower risk of serious lower GI events than traditional NSAIDs. It is now under debate, who should receive COX-2-selective inhibitors instead of classical NSAIDs, since Coxibs are much more expensive. Data from cost-effectiveness studies suggest, that Coxibs should currently be used only in patients with high risks of GI complications.

Animals↗
PubMed2003

Glucagon-like peptide 2 function in domestic animals.

Glucagon-like peptide 2 (GLP-2) is a member of family of peptides derived from the proglucagon gene expressed in the intestines, pancreas and brain. Tissue-specific posttranslational processing of proglucagon leads to GLP-2 and GLP-1 secretion from the intestine and glucagon secretion from the pancreas. GLP-2 and GLP-1 are co-secreted from the enteroendocrine L-cells located in distal intestine in response to enteral nutrient ingestion, especially carbohydrate and fat. GLP-2 secretion is mediated by direct nutrient stimulation of the L-cells and indirect action from enteroendocrine and neural inputs, including GIP, gastrin-releasing peptide (GRP) and the vagus nerve. GLP-2 is secreted as a 33-amino acid peptide and is rapidly cleaved by dipeptidylpeptidase IV (DPP-IV) to a truncated peptide which acts as a weak agonist with competitive antagonistic properties. GLP-2 acts to enhance nutrient absorption by inhibiting gastric motility and secretion and stimulating nutrient transport. GLP-2 also suppresses food intake when infused centrally. The trophic actions of GLP-2 are specific for the intestine and occur via stimulation of crypt cell proliferation and suppression of apoptosis in mucosal epithelial cells. GLP-2 reduces gut permeability, bacterial translocation and proinflammatory cytokine expression under conditions of intestinal inflammation and injury. The effects of GLP-2 are mediated by a G-protein-linked receptor that is localized to the intestinal mucosa and hypothalamus. The intestinal localization of the GLP-2R to neural and endocrine cells, but not enterocytes, suggests that its actions are mediated indirectly via a secondary signaling mechanism. The implications of GLP-2 in domestic animal production are largely unexplored. However, GLP-2 may have therapeutic application in treatment of gastrointestinal injury and diarrheal diseases that occur in developing neonatal and weanling animals.

Amino Acid Sequence↗
PubMed2001

Ulcerative proctitis, rectal prolapse, and intestinal pseudo-obstruction in transgenic mice overexpressing hepatocyte growth factor/scatter factor.

Hepatocyte growth factor/scatter factor (HGF/SF) can stimulate growth of gastrointestinal epithelial cells in vitro; however, the physiological role of HGF/SF in the digestive tract is poorly understood. To elucidate this in vivo function, mice were analyzed in which an HGF/SF transgene was overexpressed throughout the digestive tract. Nearly a third of all HGF/SF transgenic mice in this study (28 of 87) died by 6 months of age as a result of sporadic intestinal obstruction of unknown etiology. Enteric ganglia were not overtly affected, indicating that the pathogenesis of this intestinal lesion was different from that operating in Hirschsprung's disease. Transgenic mice also exhibited a rectal inflammatory bowel disease (IBD) with a high incidence of anorectal prolapse. Expression of interleukin-2 was decreased in the transgenic colon, indicating that HGF/SF may influence regulation of the local intestinal immune system within the colon. These results suggest that HGF/SF plays an important role in the development of gastrointestinal paresis and chronic intestinal inflammation. HGF/SF transgenic mice may represent a useful model for the study of molecular mechanisms associated with a subset of IBD and intestinal pseudo-obstruction. Moreover, our data identify previously unappreciated side effects that may be encountered when using HGF/SF as a therapeutic agent.

Animals↗